Burden of Congenital CMV Infection: A Narrative Review and Implications for Public Health Interventions

Cytomegalovirus causes the most common congenital infection worldwide. With most infants asymptomatic at birth, the few affected may present with variable clinical scenarios, from isolated hearing loss to severe neurologic impairment. Public health interventions include all actions at the health system, community, and individual levels that aim at reducing the burden of congenital Cytomegalovirus. This review examines the literature on maternal and neonatal screening programs in light of current evidence for treatment and the development of vaccines against Cytomegalovirus. Potential biases and benefits of these interventions are outlined, with the objective of increasing awareness about the problem and providing readers with data and critical tools to participate in this ongoing debate.


Introduction
The burden of congenital CMV infection (cCMV) is related to the sequelae of fetal invasion, possibly leading to irreversible complications.In screened populations, 40 up to 58% of symptomatic and 13.5% of asymptomatic infants at birth develop permanent sequelae [1].Neurologic sequelae, including sensorineural hearing loss (SNHL), are mostly limited to the acquisition of primary infection during the first trimester of pregnancy [2][3][4], and symptomatic newborns seem at higher risk for developing delayed-onset SNHL [5].Although treatment for cCMV has been used for more than 20 years, evidence is still weak, with data coming from a few clinical trials (from the Collaborative Antiviral Study Group-CASG) and observational studies [6][7][8][9].Based on current evidence, treatment is considered for symptomatic infected children with severe disease or with at least one organ involved [10].In Europe, no treatment is indicated in asymptomatic children or mild disease cases [11].In fact, all treatment studies excluded asymptomatic children, so no recommendation is available for this category.Given the lack of evidence, some European experts suggest treating isolated SNHL cases.In the same way, weak data denote antiviral utilization for delayed-onset SNHL [12,13], with some ongoing trials [14,15].Regarding the treatment of pregnant mothers, no evidence strongly indicates the need for antiviral therapy.However, valacyclovir therapy of periconceptional or first-trimester primary CMV infection seems to reduce vertical transmission and neonatal infections [16].Hyperimmune CMV globulin seem to have a role in decreasing the inflammatory response to CMV and subsequent tissue damage [17].
Viruses 2024, 16, 1311 2 of 17 Being the most widespread congenital infection, several public health interventions aiming at reducing the burden of disease have been proposed (or rejected) by health systems and public authorities, leaving space for wide debates still without a clear answer.Public intervention should include the epidemiology and surveillance of the disease, outreach to the population of interest (pregnant women), screening programs, health teaching, vaccination plans, and policy development (Figure 1).The aim of this review is to critically appraise public health interventions reported in the existing literature to reduce the burden of cCMV, with a special focus on neonatal screening studies and vaccine development.Hyperimmune CMV globulin seem to have a role in decreasing the inflammatory response to CMV and subsequent tissue damage [17].
Being the most widespread congenital infection, several public health interventions aiming at reducing the burden of disease have been proposed (or rejected) by health systems and public authorities, leaving space for wide debates still without a clear answer.Public intervention should include the epidemiology and surveillance of the disease, outreach to the population of interest (pregnant women), screening programs, health teaching, vaccination plans, and policy development (Figure 1).The aim of this review is to critically appraise public health interventions reported in the existing literature to reduce the burden of cCMV, with a special focus on neonatal screening studies and vaccine development.

Materials and Methods
To explore cCMV public awareness strategies, a literature search on PubMed was conducted between January 2000 and December 2023 and on national and international society websites in 2024.This search was restricted to original English-language studies and websites.
Concerning neonatal screening, studies focusing solely on epidemiological aspects or on the performance of different diagnostic methods were excluded.Additionally, studies where the targeted population was identified based only on maternal history or neonatal clinical suspicion of infection were excluded.It is reasonable to assume that these infants would be tested regardless and thus would not benefit from a screening program.
Vaccine studies for CMV were included if they involved the population of interest (adolescents, children, and women of childbearing age).Vaccine studies on transplant recipients and phase 1 trials were excluded.

Materials and Methods
To explore cCMV public awareness strategies, a literature search on PubMed was conducted between January 2000 and December 2023 and on national and international society websites in 2024.This search was restricted to original English-language studies and websites.
Concerning neonatal screening, studies focusing solely on epidemiological aspects or on the performance of different diagnostic methods were excluded.Additionally, studies where the targeted population was identified based only on maternal history or neonatal clinical suspicion of infection were excluded.It is reasonable to assume that these infants would be tested regardless and thus would not benefit from a screening program.
Vaccine studies for CMV were included if they involved the population of interest (adolescents, children, and women of childbearing age).Vaccine studies on transplant recipients and phase 1 trials were excluded.

Awareness and Education in Pregnancy
The greatest risk to pregnant women is exposure to the urine or saliva of young children.Information on CMV disease in pregnancy would properly engage the women in prevention strategies, strengthening hygienic precautions that will reduce the possibility of CMV infections among others [19][20][21][22].Physicians and obstetricians should raise awareness and provide education, these actions still being largely unpracticed [23].A systematic review by Barber et al. on the pregnancy prevention of CMV acquisition through hygiene-based behavioral interventions showed that preventive and hygienic measures are acceptable to pregnant women and have the potential to reduce the risk of infection during pregnancy [24].In the latest update of the National Institute for Health and Care Excellence (NICE) guidelines for antenatal care, it is recommended that at the first antenatal appointment, women are provided with information on infections that can impact pregnancy, including CMV, and that their personal risk factors and concerns (such as occupation and living with other children) are discussed [25].
The Center for Disease Control and Prevention (CDC) offers a dedicated website providing information to parents about the disease and its prevention, with fact sheets and an infographic [26].CDC since 2020 is promoting a CMV Awareness Month to increase awareness.
In the UK, the "CMV Action" organization promotes knowledge, supports families, and promotes scientific advances in the field of congenital CMV [27].Such great initiatives are still rare and are of paramount importance in terms of general awareness.

Maternal Screening
The identification of CMV infection during pregnancy can cause significant maternal anxiety because of the uncertainty of what the significance of the disease will be and leads to more testing and the possible (unnecessary) termination of pregnancy [28].Practices about maternal screening are heterogeneous in the absence of an international consensus and recommendations [29].Several considerations need to be carried out when balancing the feasibility of maternal serologic screening.First of all, almost half of congenital infections occur as non-primary maternal infection with CMV rather than primary infection, even if the risk of vertical transmission is lower in this case (<3.5% in CMV-seropositive mothers versus 32% during primary infection [30]).Reinfection is, however, the main modality of acquiring cCMV in high-seroprevalence populations, which are mostly low-middle income countries [31].In the United States of America, only 25% of infants with cCMV were attributable to a primary maternal infection, with three quarters of cases born to immune mothers [32].Secondly, invasive testing procedures (amniotic fluid PCR and viral culture combined) yield almost 100% positive and negative predictive values for congenital infection [20], but an association between viral loads and symptomatic infection at birth is debated, with no clear evidence [33].If reinfection is at a lower risk for mother-to-child transmission, infants born to immune mothers are still at risk of symptomatic infection and SNHL.This was shown in a Brazilian prospective study (with a 96.7% CMV-immune population rate), where 60% of SNHL affected infants were born to a mother with non-primary CMV infection [34].Maternal serologic screening alone therefore misses a considerable part of vertical infections and affected children.With these uncertainties, guidelines until now have suggested against the universal screening of CMV during pregnancy [29].However, the recently published consensus from the European Congenital Cytomegalovirus Initiative made important recommendations on treatment options for pregnant women with primary CMV infection, suggesting valacyclovir therapy and, in some instances, considering CMV hyperimmune globulin.These recommendations are based on available studies.Two randomized controlled trials on the use of CMV hyperimmune globulin during pregnancy did not show a reduction in the vertical transmission of the infection or clinical outcomes at birth [35,36].However, in a trial carried out by Revello, a reduction in vertical transmission from 40% to 30% was observed, even if not reaching significance because of the limited sample size.On the other hand, the utilization of hyperimmune globulin was associated with an increased incidence of obstetrical adverse effects [35].Some earlier data suggest the potential role of CMV hyperimmune globulin in reducing the risk of poor clinical outcomes during infant follow-up [37][38][39].In the same way, a retrospective database study showed that high-dose hyperimmune globulin administration was associated with a lower rate of fetal infection [40].In recent years, studies on valacyclovir have shown promising results in reducing the rate of vertical transmission [16,[41][42][43].Other antivirals have shown ex vivo efficacy in first-trimester placental trophoblast cell cultures and third-trimester placental explant histocultures [44].With these treatment options, maternal screening in the first trimester becomes crucial to identify women who would most likely benefit from treatments and to enhance hygiene measures and education for seronegative women [17].

Neonatal Screening
The screening of neonates would identify all children suffering from this condition.Available methods (PCR on saliva and urine) are, in fact, highly sensitive and specific.Universal screening for CMV at birth is not currently included in legislation in most countries.A debate among experts was raised in recent decades due to the potential benefit of this action (diagnosis, treatment, and follow-up), which was counter-balanced by the fact that most infections are asymptomatic and evidence for treatment does not demonstrate a strong benefit [9].
Many countries, regarding law indications or internal local practice, are adopting targeted CMV screening for infants failing the neonatal hearing screening (NHS).Currently, many countries adopt NHS [45] through evoked otoacoustic emissions (OAEs) or an automated measurement of auditory brainstem responses (ABRs), recommended for all infants before the age of three months in the United States, the United Kingdom, and Europe [46].

Universal Screening
The studies included are summarized in Table 1.Universal screening would diagnose asymptomatic babies, including isolated SNHL or asymptomatic abnormal brain findings.In the most numerous series from Fowler (USA), 8% of cCMV cases were found with isolated SNHL [47].Other smaller studies obtained variable percentages, from 0 to 10%.In the study by Lorenzoni et al., universal screening was performed on premature and small-for-gestational-age newborns, revealing an increased incidence of cCMV and isolated SNHL (17%) [48].The treatment and clinical outcomes of these children are largely unreported in the series analyzed: only four studies reported treatment and short-term outcomes.For this reason, coupled with the uncertainty of valganciclovir efficacy in asymptomatic infants, the long-term clinical significance of universal screening is hard to estimate.Larger, prospective, and longer studies of coupled universal screening with therapeutic trials would further clarify the benefit.Viruses 2024, 16, 1311 7 of 17

Targeted Screening
The studies included are reported in Table 2.
Regarding targeted screening studies, they were mainly retrospective experiences from centers locally performing cCMV screening for infants failing NHS.The primary limitation in understanding the potential of screening is that most studies did not exclude symptomatic infants or those with known or suspected maternal infection during pregnancy.Even when considering isolated cases of sensorineural hearing loss (SNHL), these could still originate from mothers with known infections and be diagnosed without screening.Clinical outcomes are available from only two studies [57,58].Furthermore, concerns exist regarding the sensitivity of hearing tests performed at birth.False negatives could result in missing cases of neonatal hearing loss, thereby depriving these children of the benefits of both pharmacological and non-pharmacological therapies and precluding early intervention for those with delayed-onset SNHL.
A prospective study by Fowler enrolled 443 children with cCMV identified through universal neonatal screening over 5 years: 35 newborns were diagnosed with SNHL by a confirmatory hearing test [47].Of these 35 newborns, 15 (43%) passed their hearing screening.In this study, therefore, targeted screening missed 43% of cCMV with a neonatal-onset hearing deficit.One neonate out of two and one neonates out of four with confirmed SNHL passed the HS in the series from Dar (India) and Yamamoto (Brazil), respectively [51,52].
Another aspect that emerged during the search is that some infants classified as symptomatic within screening programs are, in practice, asymptomatic at birth.They are deemed symptomatic only due to laboratory abnormalities or abnormal cerebral findings that would otherwise remain undiagnosed [49,53,59].
In this context, it is worth questioning whether an asymptomatic newborn is truly 'asymptomatic'.The significance of nonspecific ultrasound or MRI findings, such as isolated lenticulostriatal vasculopathy, remains uncertain, and the long-term outcomes associated with these findings are still unknown [11].The follow-up of diagnosed cases would lead to the development of a scoring system aimed at more accurately quantifying the risk of adverse outcomes.This would expand the knowledge base to facilitate studies on treatment.
From the scant clinical data and follow-up availability in the search, it is hard to extrapolate a long-term clinical outcome of targeted and universal screening for cCMV.This would be clarified in the occurrence of clear treatment indications and evidence of efficacy.However, mainly due to the paucity of data and the fact that most cCMV cases are mild, large trials of treatment are missing, and recommendations are weak.

Vaccinations
Key factors considered in the vaccine prioritization strategies include disease burden, vaccine effectiveness and safety, the feasibility of additional recommendations in the context of the existing vaccination schedule, equity of access, and whether vaccination is a good use of public funds [70].
Cytomegalovirus is not highly contagious, and it is believed that protecting 50-60% of the population could lead to viral elimination, making vaccination cost effective [71].Several efforts are currently focused on vaccine development, with some aimed at preventing infection in transplant patients and others targeting the prevention of congenital infection [72].
Regarding cCMV disease, vaccination efforts should focus on protecting women of childbearing age from acquiring the infection.To achieve this goal, the target population should primarily include young women, adolescents, and young children as they are the main sources of infection for pregnant mothers [73].
Here is a summary of vaccines studied in the population of interest, which includes adolescents, children, and women of childbearing age (Table 3).Studies on transplant recipients and phase 1 trials are excluded from this summary.
Three CMV vaccines have reached phases 2 and 3 in healthy individuals.The MF59adjuvated recombinant CMV glycoprotein B vaccine was studied in two phase 2 trials in post-partum seronegative women and adolescents [74,75].While in the first study, the vaccine's effectiveness in preventing the infection in post-partum women seemed good [74], in the second study on adolescents, it was not significant.No phase 3 trial is ongoing.V160 is a whole-virus vaccine derived from the live-attenuated AD169 strain.A recently published phase 2 trial by Das was terminated early because of the futility in preventing the primary CMV infection in vaccinated women compared to the placebo [76].The mRNA-1647 vaccine seem to induce higher neutralization and antibody-dependent cellular cytotoxicity responses compared to the gB/MF59 vaccine [77].A phase 2 trial of the CMV mRNA-1647 vaccine was terminated in 2023 [78].The results are not available, but in 2020, the company declared a positive seven-month interim safety and immunogenicity analysis.The following phase 3 trial is expected to evaluate the efficacy of the vaccine in a larger population of healthy individuals at risk of having early post-vaccination contact with young children (NCT05085366) [79].Moreover, 7545 patients were enrolled, but the results have still not been reported.
The immunogenicity of CMV vaccines has not been studied in young children.This is due to the lack of positive effectiveness data on adults, unknown duration of immunity, and mildness of the disease in infancy [73].

Final Considerations and Future Prospectives
Despite being a widespread disease with a substantial body of literature addressing congenital CMV, evidence regarding the effectiveness of various interventions remains weak.The absence of effective treatment options for asymptomatic children or LO-SNHL complicates the implementation of screening by health systems.This underscores the need, at higher levels, to weigh the allocation of public funds against numerous competing health priorities.The promotion of trials during pregnancy is primarily hindered by ethical concerns, which limits the advancement of therapeutic strategies to prevent fetus damages by CMV infection.It is crucial to enhance education among pregnant women and increase awareness among healthcare providers about congenital CMV at the community, local, and national organizational levels.Early education remains, in fact, the main useful strategy to prevent primary maternal infection during pregnancy, and awareness initiatives should be supported by health systems.
To date, vaccine research has predominantly focused on immunosuppressed patients, and data regarding healthy women do not demonstrate significant effectiveness.The network between gynecologists, obstetricians, infectious disease specialists and pediatric infectious disease teams for managing mother-infant pairs should be strengthened and established as the standard of care for cCMV by public health systems.In this view, maternal and neonatal universal screening emerges as a possible way forward, along with continued research on vaccines.It would ease the understanding of risk factors for infection and sequelae (such as prematurity, low birth weight, and brain imaging anomalies), the development of scoring systems, and the optimization of follow-up modalities.This would allow researchers to construct a basis for new therapeutic trials.

Figure 1 .
Figure 1.Preventive public measures proposed to reduce the cCMV burden.Adapted from Public Health Interventions (population-based), Minnesota Department of Health [18].

Figure 1 .
Figure 1.Preventive public measures proposed to reduce the cCMV burden.Adapted from Public Health Interventions (population-based), Minnesota Department of Health [18].

Table 3 .
Summary of studies (published or ongoing) included on vaccination for CMV.Nab: neutralizing antibody.